Diastereoselective synthesis of meso-bisphosphonates from trialkyl(aryl) phosphites and activated acetylenes in the presence of 4-nitrophenol

Article abstract of DOI:10.1007/s00706-006-0502-4

The reaction between trialkyl(aryl) phosphites and dibenzoylacetylene or dimethyl acetylenedicarboxylate in the presence of 4-nitrophenol leads to stable meso-bisphosphonate derivatives in good yields. Springer-Verlag 2006.

Full text of DOI:10.1007/s00706-006-0502-4

Monatshefte f€ur Chemie 137, 1083–1088 (2006)
DOI 10.1007/s00706-006-0502-4
Diastereoselective Synthesis of meso-
Bisphosphonates from Trialkyl(aryl)
Phosphites and Activated Acetylenes
in the Presence of 4-Nitrophenol
ꢀ
Issa Yavari , Zinatossadat Hossaini, and Abdolali Alizadeh
Department of Chemistry, Tarbiat Modarres University, Tehran, Iran
Received November 24, 2005; accepted (revised) January 23, 2006
Published online August 3, 2006 # Springer-Verlag 2006
Summary. The reaction between trialkyl(aryl) phosphites and dibenzoylacetylene or dimethyl acet-
ylenedicarboxylate in the presence of 4-nitrophenol leads to stable meso-bisphosphonate derivatives in
good yields.
Keywords. Bisphosphonates; Activated acetylenes; Trialkyl phosphites; Stereoselective synthesis.
Introduction
Organophosphorus compounds are versatile intermediates in synthetic chemistry
[1–3]. In particular, organophosphonates that possess a C–P bond have found to be
useful reagents, have a varied biological activity, and are useful in material chem-
istry [4–6]. As a result, a large number of methods have appeared describing novel
syntheses of bisphosphonate systems [7–10]. There are also many studies on the
reaction between trivalent phosphorus nucleophiles and ꢀ,ꢁ-unsaturated carbonyl
compounds in the presence of a proton source, such as alcohol or phenol [11–13].
A recent paper of Balaraman and Kumaraswamy [11] intrigued us to present
our work on the diastereoselective synthesis of meso-bisphosphonates through
the reaction of trialkyl(aryl) phosphites and activated acetylenes in the presence
of 4-nitrophenol.
Results and Discussion
The reaction of trialkyl(aryl) phosphites 2 with dibenzoylacetylene (DBA, 1a) in
the presence of 4-nitrophenol (3) as the proton source=nucleophile leads to dialkyl
ꢀ
Corresponding author. E-mail: yavarisa@modares.ac.ir

1084
I. Yavari et al.
Scheme 1
[1-benzoyl-2- (dialkoxyphosphoryl)-3-oxo-3-phenylpropyl]phosphonates 4a–4c in
good yields. Similarly, dimethyl 2,3-bis(dialkoxyphosphoryl)succinates 4d–4f
were prepared in good yields using dimethyl acetylenedicarboxylate (DMAD,
1b) as the activated acetylenic compound (Scheme 1).
The structures of bisphosphonates 4a–4f and 5a–5b were deduced from their
1
elemental analyses and their IR, H, 13C, and 31P NMR, and mass spectral data.
The mass spectra of these compounds displayed molecular ion peaks at appropriate
1
m=z values. The H NMR spectrum of 4a in CDCl3 showed two doublets at
ꢂ ¼ 3.42 (3JHP ¼ 10.1 Hz) and 3.64 (3JHP ¼ 9.1 Hz) for the diastereotopic methoxy
groups and a doublet of doublet at ꢂ ¼ 5.22 (2JHP ¼ 10.6 Hz and 3JHH ¼ 7.9 Hz) for
the methine protons, along with multiplets at ꢂ ¼ 7.46–8.06 ppm for the aromatic
moieties. A single resonance at ꢂ ¼ 194.2 ppm is observed in the 13C NMR spec-
trum of 4a, which is attributed to the carbonyl groups. The 31P NMR signal of 4a
was found at ꢂ ¼ 23.23 ppm. The 1H and 13C NMR spectra of 4b and 4c are similar
to those of 4a except for the phosphoranyl moieties. The 1H NMR spectrum of 4d in
CDCl3 showed two doublets at ꢂ ¼ 3.22 (3JHP ¼ 8.7 Hz) and 3.41 (3JHP ¼ 8.2 Hz)
for the diastereotopic methoxy groups and a doublet of doublet at ꢂ ¼ 4.75
3
(2JHP ¼ 11.2 Hz and JHH ¼ 8.1 Hz) for the methine moieties, along with a singlet
at ꢂ ¼ 3.81 ppm for the two CO2Me groups. The ester carbonyl resonances in the
13C NMR spectra of 4d appear as a singlet at ꢂ ¼ 167.4 ppm in the 13C NMR
Scheme 2

Diastereoselective Synthesis of meso-Bisphosphonates
1085
Scheme 3
spectrum. The 31P NMR signal of 4d was found at ꢂ ¼ 19.58 ppm. The 1H and 13
C
NMR spectra of 4e and 4f are similar to those of 4d except for the phosphoranyl
moieties.
Assignment of the meso structure to compounds 4 (Scheme 2) is based on the
13C NMR spectra [11]. Whereas the P–CH carbon atoms of the meso diastereo-
isomer exhibits a 5-line pattern (A part of AXX0 system; X ¼ X0 ¼ phosphorus), a
simple doublet is expected for the dl form [11]. The meso structure represents a
high field limiting case which does not give a ‘‘first order’’ spectrum. Thus, some
mixing of the basic functions is involved [14]. The RC¼O carbon of the meso form
2,3
2,3
appears essentially as a singlet (fairly small
J
PC
a multiplet (a doublet of doublet due to the higher
values), but the dl form exhibits
J
PC
values).
Although we have not yet established the mechanism of the reaction between
trialkyl(aryl) phosphites and acetylenes in the presence of 4-nitrophenol in an
experimental manner, a plausible explanation is proposed in Scheme 3. On the
basis of the well established chemistry of phosphorus nucleophiles [1–3], it is
reasonable to assume that compounds 4 result from initial addition of phosphite
to the activated acetylene and subsequent protonation of the reactive 1:1 adduct by
4-nitrophenol, followed by attack of the phenoxide ion at the alkyl group of the
phosphite to generate 9 and 1-alkoxy-4-nitrobenzene 5. Because of the higher
nucleophilicity of phosphites compared to the conjugate base of 4-nitrophenol,
intermediate 9 is attacked by a second phosphorus nucleophile.
The present method carries the advantage that, not only is the reaction performed
under neutral conditions, but the educts can be mixed without any activation or
modification. The simplicity of the present procedure for diastereoselective synthe-
sis of bisphosphonates makes it an interesting alternative to complex multistep
approaches.
Experimental
Dibenzoylacetylene was prepared according to Refs. [15, 16]. Other chemicals were purchased from
Fluka and used without further purification. Melting points were measured on an Electrothermal 9100
aparatus. Elemental analyses for C, H, and N were performed using a Heraeus CHN-O-Rapid analyzer.
The results agreed favorably with the calculated values. Mass spectra were recorded on a FINNIGAN-

1086
I. Yavari et al.
MATT 8430 spectrometer operating at an ionization potential of 70eV. IR spectra were measured on a
Shimadzu IR-460 spectrometer. 1H, 13C, and 31P NMR spectra were measured with a BRUKER DRX-
500 AVANCE spectrometer at 500.1, 125.8, and 202.4 MHz.
Dimethyl [1-benzoyl-2-(dimethoxyphosphoryl)-3-oxo-3-phenylpropyl]phosphonate
(4a, C20H24O8P2)
Typical procedure: To a stirred solution of 0.23 g DBA (1mmol) and 0.28 g 4-nitrophenol (2mmol) in
10cm3 CH2Cl2 was added 0.25 g trimethyl phosphite (2mmol) at room temperature. The reaction
mixture was then stirred for 24h. The solvent was removed under reduced pressure and the viscous
residue was purified by preparative TLC on silica gel column chromatography (Merck 230–400 mesh)
using n-hexane-EtOAc as eluent to give 4a as white powder, mp 158–160ꢁC, yield 0.39g, 86%; IR
(KBr): ꢃꢀ¼ 2950, 1667, 1584, 1258, 1015 cmꢂ1
;
1H NMR (500 MHz, CDCl3): ꢂ ¼ 3.42 (6 H, d,
3
2
3JHP ¼ 10.1Hz, 2 OMe), 3.64 (6 H, d, JHP ¼ 9.1 Hz, 2 OMe), 5.22 (2 H, dd, JHP ¼ 10.6Hz and
3JHH ¼ 7.9 Hz, 2 CH), 7.47 (4 H, t, 3JHH ¼ 7.2 Hz, 4 CHmeta of 2 C6H5), 7.55 (2 H, t, 3JHH ¼ 6.4 Hz, 2
3
CHpara of 2 C6H5), 8.05 (4 H, d, JHH ¼ 7.4 Hz, 4 CHortho of 2 C6H5) ppm; 13C NMR (125.7MHz,
CDCl3): ꢂ ¼ 45.9, 46.2, 46.6, 47.2, 47.5 (5 lines for P–CH), 53.4 (d, 2JCP ¼ 3.1 Hz, 2 OCH3), 53.5 (d,
2JCP ¼ 3.3 Hz, 2 OCH3), 128.6 (s, 4 CH of C6H5), 128.7 (s, 4 CH of 2 C6H5), 133.3 (s, 2 CH of 2
C6H5), 137.1 (s, 2 Cipso of 2 C6H5), 194.2 (s, C¼O) ppm; 31P NMR (202MHz, CDCl3): ꢂ ¼ 23.23
(P¼O) ppm; MS (EI, 70 eV): m=z (%) ¼ 454 (Mþ, 10), 423 (15), 349 (64), 344 (38), 227 (10), 196
(24), 110 (58), 105 (100), 31 (86).
Diethyl [1-benzoyl-2-(diethoxyphosphoryl)-3-oxo-3-phenylpropyl]phosphonate
(4b, C24H32O8P2)
White powder, mp 167–169ꢁC, yield 0.45 g, 88%; IR (KBr): ꢃꢀ¼ 2925, 1675, 1584, 1254, 1024 cmꢂ1
;
1H NMR (500MHz, CDCl3): ꢂ ¼ 1.25 (12 H, t, 3JHH ¼ 7.0 Hz, 4 Me), 4.03 (8 H, m, 4 OCH2), 4.72 (2 H,
dd, 2JHP ¼ 14.7 Hz and 3JHH ¼ 10.2 Hz, 2 CH), 7.41 (4 H, t, 3JHH ¼ 7.7 Hz, 4 CHmetha of 2 C6H5), 7.55
3
3
(2 H, t, JHH ¼ 6.4 Hz, 2 CHpara of 2 C6H5), 8.03 (4 H, d, JHH ¼ 7.9 Hz, 4 CHortho of 2 C6H5) ppm;
13C NMR (125.7 MHz, CDCl3): ꢂ ¼ 16.0 (d, JCP ¼ 6.5 Hz, 2 CH3), 16.2 (d, JCP ¼ 5.97 Hz, 2 CH3),
47.5, 47.8, 48.6, 49.3, 40.5 (5 lines for P–CH), 62.9 (d, 2JCP ¼ 6.7 Hz, 2 OCH2), 63.5 (d, 2JCP ¼ 5.9 Hz,
2 OCH2), 128.5 (s, 4 CH of C6H5), 128.6 (s, 4 CH of 2 C6H5), 133.3 (s, 2 CH of 2 C6H5), 135.8 (s, 2 Cipso
of 2 C6H5), 195.23 (s, C¼O) ppm; 31P NMR (202MHz, CDCl3): ꢂ ¼ 22.39 (P¼O) ppm; MS (EI, 70eV):
m=z (%) ¼ 510 (Mþ, 5), 465 (25), 405 (52), 373 (28), 255 (24), 137 (10), 105 (100), 45 (75).
3
3
Diphenyl [1-benzoyl-2-(diphenoxyphosphoryl)-3-oxo-3-phenylpropyl]phosphonate
(4c, C40H32O8P2)
Colorless crystals, mp 185–187ꢁC, yield 0.61 g, 87%; IR (KBr): ꢃꢀ¼ 2920, 1673, 1581, 1252,
1
2
3
1014 cmꢂ1; H NMR (500 MHz, CDCl3): ꢂ ¼ 4.23 (2 H, dd, JHP ¼ 11.6Hz and JHH ¼ 10.7Hz, 2
3
3
CH), 7.08 (4 H, t, JHH ¼ 8.0 Hz, 4 CHpara of 4 OC6H5), 7.09 (8 H, d, JHH ¼ 8.5 Hz, 8 CHortho of 4
3
3
OC6H5), 7.17 (8 H, dd, JHH ¼ 7.6 Hz, JHH ¼ 7.9 Hz, 8 CHmeta of 4 OC6H5), 7.37 (4 H, t,
3JHH ¼ 7.4 Hz, 4 CHmeta of 2 C6H5), 7.43 (2 H, t, JHH ¼ 7.2 Hz, 2 CHpara of 2 C6H5), 7.65 (4 H, d,
3
3JHH ¼ 7.3 Hz, 4 CHortho of 2 C6H5) ppm; 13C NMR (125.7 MHz, CDCl3): ꢂ ¼ 44.7, 45.4, 45.9, 46.4,
46.8 (5 lines for P–CH), 120.8 (d, 3JCP ¼ 4.9, 8 CH of 4 OC6H5), 125.0 (s, 8 CH of 4 OC6H5), 128.2 (s,
4 CH of 2 OC6H5), 129.5 (s, 4 CH of 2 C6H5), 129.7 (s, 4 CH of 2 C6H5), 130.5 (s, 2 CH of 2 C6H5),
2
2
150.4 (s, 2 Cipso of 2 C6H5), 162.4 (d, JPC ¼ 15.0Hz, 2 Cipso of 2 OC6H5), 162.6 (d, JPC ¼ 15.2Hz,
2 Cipso of 2 OC6H5), 194.2 (s, C¼O) ppm; 31P NMR (202MHz, CDCl3): ꢂ ¼ 11.02 (P¼O) ppm; MS
(EI, 70eV): m=z (%) ¼ 702 (Mþ, 5), 469 (15), 351 (35), 236 (38), 233 (38), 105 (100), 93 (85), 77 (86).
Dimethyl 2,3-bis(dimethoxyphosphoryl)succinate (4d, C10H20O10P2)
White powder, mp 73–74ꢁC, yield 0.32g, 88%; IR (KBr): ꢃꢀ¼ 2922, 1720, 1583, 1259, 1154,
1
3
1024 cmꢂ1; H NMR (500 MHz, CDCl3): ꢂ ¼ 3.22 (6 H, d, JHP ¼ 8.7Hz, 2 OMe), 3.41 (6 H, d,

Diastereoselective Synthesis of meso-Bisphosphonates
1087
2
3
3JHP ¼ 8.2 Hz, 2 OMe), 3.81 (6 H, s, 2 CO2Me), 4.75 (2 H, dd, JHP ¼ 11.2 Hz and JHH ¼ 8.1 Hz,
2 CH) ppm; 13C NMR (125.7MHz, CDCl3): ꢂ ¼ 42.9, 43.2, 43.7, 44.2, 44.5 (5 lines for P–CH), 52.4
(d, 2JCP ¼ 3.5 Hz, 2 POCH3), 52.8 (d, JCP ¼ 3.8 Hz, 2 POCH3), 55.6 (s, 2 CO2CH3), 167.4 (s, C¼O)
2
31
ppm; P NMR (202MHz, CDCl3): ꢂ ¼ 19.58 (P¼O) ppm; MS (EI, 70eV): m=z (%) ¼ 362 (Mþ, 5),
331 (35), 253 (20), 181 (48), 110 (100), 31 (78).
Dimethyl 2,3-bis(diethoxyphosphoryl)succinate (4e, C14H28O10P2)
White powder, mp 85–87ꢁC, yield 0.35g, 83%; IR (KBr): ꢃꢀ¼ 2920, 1731, 1589, 1261, 1158,
1
3
1029 cmꢂ1; H NMR (500MHz, CDCl3): ꢂ ¼ 1.21 (12 H, t, JHH ¼ 7.0 Hz, 4 Me), 3.60 (2 H, dd,
2JHP ¼ 10.2Hz and 3JHH ¼ 8.1 Hz, 2 CH), 3.83 (6 H, s, 2 OMe), 4.01 (8 H, m, 4 OCH2) ppm; 13C NMR
3
3
(125.7 MHz, CDCl3): ꢂ ¼ 15.8 (d, JCP ¼ 6.9 Hz, 2 CH3), 15.9 (d, JCP ¼ 6.7 Hz, 2 CH3), 39.2, 39.5,
2
40.3, 41.2, 41.8 (5 lines for P–CH), 54.6 (s, 2 OCH3), 62.9 (d, JCP ¼ 5.9 Hz, 2 OCH2), 63.5 (d,
2JCP ¼ 5.8 Hz, 2 OCH2), 168.6 (s, C¼O) ppm; 31P NMR (202MHz, CDCl3): ꢂ ¼ 21.09 (P¼O) ppm;
MS (EI, 70 eV): m=z (%) ¼ 418 (Mþ, 6), 387 (10), 251 (20), 223 (96), 209 (10), 138 (48), 113 (100),
45 (78).
Dimethyl 2,3-bis(diphenoxyphosphoryl)succinate (4f, C30H28O10P2)
Colorless crystals, mp 173–175ꢁC, yield 0.52g, 85%; IR (KBr): ꢃꢀ¼ 2950, 1739, 1581, 1277, 1246,
1
2
1184, 1155 cmꢂ1; H NMR (500MHz, CDCl3): ꢂ ¼ 3.75 (6 H, s, OMe), 4.33 (2 H, dd, JHP ¼ 12Hz
and 3JHH ¼ 6.0Hz, CH), 7.16 (4 H, t, 3JHH ¼ 8.0 Hz, 4 CHpara of 4 C6H5), 7.25 (8 H, d, 3JHH ¼ 5.7 Hz,
3
3
8 CHortho of 4 C6H5), 7.31 (8 H, dd, JHH ¼ 8.4 Hz and JHH ¼ 7.5 Hz, 8 CHmeta of 4 C6H5) ppm;
13C NMR (125.7MHz, CDCl3): ꢂ ¼ 44.4, 44.7, 45.2, 45.7, 46.0 (5 lines for P–CH), 53.3 (2 OCH3),
3
4
120.8 [d, JCP ¼ 7.5, 8 CHortho of (C6H5O)2PO], 125.6 [d, JPC ¼ 2.5 Hz, CHmeta of (C6H5O)2PO],
2
129.8 [s, 4 CHpara of (C6H5O)2PO], 150.0 [d, JPC ¼ 14.6Hz, 2 Cipso of (C6H5O)2PO], 150.1 [d,
2JPC ¼ 14.4Hz, 2 Cipso of (C6H5O)2PO], 166.3 (s, C¼O) ppm; 31P NMR (202 MHz, CDCl3):
ꢂ ¼ 11.73 (P¼O) ppm; MS (EI, 70 eV): m=z (%) ¼ 610 (Mþ, 6), 579 (20), 517 (100), 485 (10), 318
(10), 285 (80), 223 (58), 140 (46), 94 (40), 77 (100).
1-Methoxy-4-nitrobenzene (5a, C7H7NO3)
Colorless crystals, mp 75–77ꢁC, yield 0.14g, 92%; IR (KBr): ꢃꢀ¼ 1683, 1492, 1333, 1261, 1173, 1105,
1
3
1016 cmꢂ1; H NMR (500 MHz, CDCl3): ꢂ ¼ 3.89 (3 H, s, OMe), 6.93 (2 H, d, JHH ¼ 9.1 Hz, 2 CH
of C6H5), 8.17 (2 H, d, 3JHH ¼ 9.2 Hz, 2 CH of C6H5) ppm; 13C NMR (125.7MHz, CDCl3): ꢂ ¼ 55.9
(s, CH3), 114.0 (s, 2 CH), 125.9 (s, 2 CH), 141.5 (s, Cipso of Ph), 164.6 (s, Cipso of Ph) ppm.
1-Ethoxy-4-nitrobenzene (5b, C8H9NO3)
Yellow crystals, mp 79–81ꢁC, yield 0.13 g, 87%; IR (KBr): ꢃꢀ¼ 1585, 1490, 1329, 1257, 1177, 1102,
3
1033 cmꢂ1
;
1H NMR (500 MHz, CDCl3): ꢂ ¼ 1.45 (3 H, t, JHH ¼ 6.9Hz, Me), 4.12 (2 H, q,
3JHH ¼ 6.9 Hz, OCH2), 6.93 (2 H, d, JHH ¼ 9.2 Hz, 2 CH of C6H5), 8.18 (2 H, d, JHH ¼ 9.2 Hz, 2
CH of C6H5) ppm; 13C NMR (125.7MHz, CDCl3): ꢂ ¼ 14.5 (s, CH3), 64.4 (s, OCH2), 114.4 (s, 2 CH
of Ph), 125. 9 (s, 2 CH of Ph), 141.4 (s, Cipso of Ph), 164.0 (s, Cipso of Ph) ppm.
3
3
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